Kv6.4

Introductions

Kv6.4 is a potassium voltage-gated channel, subfamily G, member 4, also known as KV6.4; MGC4558; MGC129609. The electrically silent Kv channel α-subunit Kv6.4 is not capable of forming functional homotetrameric channels; however, it can heterotetramerize with Kv2.1 α-subunits to form functional Kv2.1/Kv6.4 channel complexes, presumably in a 3[ratio]1 stoichiometry [1838]. The gene has strong expression in brain. Multiple alternatively spliced variants have been found in normal and cancerous tissues.

Transcripts

Ontologies

A protein complex that forms a transmembrane channel through which potassium ions may cross a cell membrane in response to changes in membrane potential.

IEA

GO:0016020

membrane

Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins.

IEA

Interactions

Aspartates in the T1 domain are required for efficient assembly of both homotetrameric Kv2.1 and heterotetrameric Kv2.1/silent Kv6.4 channels. [677]

Proteins

Structures

Distributions

Expressions

Functionals

Domains Required for Kv6.4 Function

It has been demonstrated that Kv2.1 chimeras containing either S1 or S5 from Kv6.4 were functional, wheras a chimeric Kv2.1 subunit containing both the Kv6.4 S1 and S5 segments did not form functional channels. However, back mutation of some residues in this S1/S5 chimera restored functionality, and it was shown that interactions between S1, S4, and S5 are important for the functionality of WT Kv2.1 (4). It is possible that the inability to form electrically functional channels in homotetrameric configuration is due to the lack of such S1/S4/S5 interactions, at least in the case of Kv6.4 [1840]

His-105 in the T1 domain of Kv2.1 is required for functional heteromerization with members of the Kv6 subfamily, such as Kv6.4.
[664]

Migraine

Several genes encoding potassium channels, including KCNK18, KCNG4, and KCNAB3, were identified as potentially linked to migraine [1839]

Kinetics

Human Kv6.4 Kinetics with Rat Kv2.1 in HEK293 Cells

Kv6.4 exerts several changes in the biophysical properties of Kv2.1 in Kv2.1/Kv6.4 channel complexes: a decrease in the current density [14] and a hyperpolarizing shift in the voltage-dependence of inactivation by ~40 mV, but without any significant effects on voltage-dependence of channel activation [15]. Here we show the modulating effects of Kv6.4 on Kv2.1 gating properties by analyzing the voltage-dependence of VSD movements in Kv2.1 and Kv2.1/Kv6.4 channels from IQ recordings. Our results suggest that Kv6.4 subunits display an intrinsic voltage-dependency with an operational VSD in heterotetrameric Kv2.1/Kv6.4 channels, by virtue of which it specifically influences the voltage-dependent inactivation properties of Kv2.1 [1838]

Kv6.4 with Kv2.1 in HEK293 Cells

Human Kv constructs were cloned in the mammalian vector peGFP-N1 (Clontech, Palo Alto, CA, USA). The Kv6.4 construct in which the C-terminus was exchanged for that of Kv3.1 as well as the N- and C-terminal segment constructs were constructed by PCR amplification using the QuickChange Site-Directed Mutagenesis kit (Stratagene La Jolla, CA, USA) and mutant primers. The main biophysical effect of WT Kv6.4 in a functional Kv2.1/Kv6.4 heterotetrameric channel is the approximately 40 mV hyperpolarizing shift in the voltage dependence of inactivation compared to Kv2.1 homotetramers. Indeed, the midpoint of inactivation for homotetrameric Kv2.1 currents was −23 mV which was shifted to −59 mV in heterotetrameric Kv2.1/Kv6.4 channels [1841]

Models

Markov Model for Kv2.1/Kv6.4 Channel Gating

For convenience we used a simplified gating model (A) with a single transition between closed (C) and activated (A) state for each subunit, followed by the concerted step into the open (O) state (after all four subunits have reached the A-state). The equivalent Markov state-model (B) was built such that it could simulate both the heterotetrameric Kv2.1/Kv6.4 channel configuration with a 3[ratio]1 stoichiometry, as well as the homotetrameric Kv2.1 channel. To represent the heterotetrameric stoichiometry the closed and activated state of the Kv6.4 subunit are indicated with asterisks (C and A, respectively) [1838]